Risultati per: Scoperta una nuova molecola anti-cancro

Objective
To estimate the herd effects of anti-microbial-based decontamination (ABD) interventions on bloodstream infections (BSIs) among groups of intensive care unit (ICU) patients in relation to group mean length of stay (LOS). To deduce which of three competing hypotheses of ABD effect mediation best accounts for the observed effects.

Design
Arms-based meta-regression of ICU-acquired BSI incidence against group mean LOS for control and interventions arms of ABD and non-ABD controlled trials each versus that in arms of observational studies.

Exposures
Within controlled trials of ABD, intervention, concurrent control (CC) and non-concurrent (NCC) groups are directly, indirectly and non-exposed, respectively.

Main outcomes and measures
BSI incidence, both overall and for BSI subtypes.

Results
In the arms-based meta-regression, the predicted BSI incidence per 100 patients in the ABD intervention arms increased from 4.6 (95% CI 3.8 to 5.5) at mean LOS 7 days to 13.0 (10.4–16.0) at mean LOS 20 days (n=60 arms) and CC arms 8.5 (6.7–11.0) increasing to 19.3 (14.8–24.8; n=52). These increases were double those in the observational (7.2; 6.1–8.5 increasing to 12.9; 10.4–16.7; n=99) and NCC arms and non-ABD arms. These results triangulate with the notional effect size observed in contrast-based meta-analyses.

Conclusions
The increased tempo of BSI acquisition, both overall and for various BSI subtypes, within intervention and CC groups of ABD randomised concurrent controlled trials versus other groups implicate rebound and spillover, respectively. Mechanisms other than colonisation resistance mediate ABD effects.

La Presidenza del Consiglio aderisce a ‘Illumina novembre’

Neurologi: ‘si apre una nuova storia per i pazienti’

Le nuove prestazioni erano attese da quasi otto anni e cioè da quando era comparsa la prima versione del tariffario poi sempre rinviato per il nodo risorse

A 5 anni dall’arrivo in Italia trattati oltre 1.400 pazienti

Objective
Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear.

Design
We established hepatocyte-specific Sqle transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry.

Results
Hepatocyte-specific Sqle tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-+ and Granzyme B+ CD8+ T cells while enriching Arg-1+ myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific Sqle knockout suppressed tumour growth with increased cytotoxic CD8+ T cells and reduced Arg-1+ MDSCs, inferring that SQLE promotes immunosuppression in MASH-HCC. Mechanistically, SQLE-driven cholesterol accumulation in tumour microenvironment underlies its effect on CD8+ T cells and MDSCs. SQLE and its metabolite, cholesterol, impaired CD8+ T cell activity by inducing mitochondrial dysfunction. Cholesterol depletion in vitro abolished the effect of SQLE-overexpressing MASH-HCC cell supernatant on CD8+ T cell suppression and MDSC activation, whereas cholesterol supplementation had contrasting functions on CD8+ T cells and MDSCs treated with SQLE-knockout supernatant. Targeting SQLE with genetic ablation or pharmacological inhibitor, terbinafine, rescued the efficacy of anti-PD-1 treatment in MASH-HCC models.

Conclusion
SQLE induces an impaired antitumour response in MASH-HCC via attenuating CD8+ T cell function and augmenting immunosuppressive MDSCs. SQLE is a promising target in boosting anti-PD-1 immunotherapy for MASH-HCC.

Circulation, Volume 150, Issue Suppl_1, Page A4136984-A4136984, November 12, 2024. .Background:Third-degree atrioventricular block (AVB) is the most common manifestation of Anti-Ro antibody associated fetal cardiac disease. Extranodal findings of isolated cardiac echogenicity, valvulitis with insufficiency and AV interval prolongation have been reported but not described in large prospective series.Aims:To report the occurrence and outcomes of extranodal findings in subjects followed prospectively since 2020 in STOP BLOQ (Surveillance and Treatment to Prevent Fetal AV block Likely to Occur Quickly) and the Registry for Neonatal Lupus (RNL).Methods:We reviewed fetal echo reports from pregnant STOP BLOQ and RNL Anti-Ro antibody subjects. Pregnancies with high ( >1000 EU for anti-Ro52 or 60) antibody titers measured in a core research lab underwent surveillance with home fetal heart rate monitoring (FHRM) 3x/day and weekly or bi-weekly fetal echos from 17- 26 gestational weeks. Low titer subjects underwent echo or no surveillance based on local site protocol. We evaluated cardiac function, effusions, cardiac echogenicity and its location, any tricuspid (TV) or mitral (MV) insufficiency trivial or >trivial) and AV conduction times (170 ms)Results:Echo reports were available in 622 prospectively followed pregnancies (376 high (40/376 with a previously affected child) and 246 low-titer pregnancies. All had subjectively normal ventricular function and none had effusions. Seven fetuses, 2 low and 5 high titer at 19 (range 16.7-21.7) weeks demonstrated cardiac echogenicity (n=6), AV or semilunar valve insufficiency (n=2) or AV interval 150-170 ms (n=2) (Table). Subjects 1 and 2, both high titer and treated with prophylactic Plaquenil (400 mg/d before 10 gestational weeks), had prior fetal AVB. Subject #1 had normal AV conduction but MV and TV echogenicity and moderate insufficiency of both valves which resolved in days after IVIG and dexamethasone (dex) treatment, but 3° AVB developed at 19 weeks after dex wean. Subjects 2-7 received no treatment and extranodal findings did not progress to cardiac dysfunction or AVB. During the same time period, 10 high titer subjects developed 2° or 3° AVB.Conclusion:Anti-Ro associated extranodal findings are rare, occurring in 1% of pregnancies overall and in 5% of pregnancies with a previously affected child. Unlike AVB, extranodal findings can occur in low titer pregnancies. The role of treatment for isolated extranodal findings in the absence of cardiac dysfunction is unclear.

Circulation, Volume 150, Issue Suppl_1, Page A4146462-A4146462, November 12, 2024. Background:Recurrent ventricular tachycardia (VT) is common in patients with ischemic heart disease (IHD), even with anti-arrhythmic drugs on board. While ICDs can abort VT episodes, ICD shocks can be painful. Ablation therapy can reduce the number of ICD shocks and interventions, but the optimal ablation technique is still uncertain.Purpose:We aim to review the clinical efficacy and safety of catheter ablation vs anti-arrhythmic drugs in patients with IHD.Methods:We conducted comprehensive searches across PubMed, CENTRAL, WOS, Scopus, and EMBASE until Feb 2024. Pooled data were reported using risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, along with a 95% confidence interval (CI). This systematic review and meta-analysis was registered with PROSPERO ID: CRD42024551760.Results:We included seven RCTs with a total of 836 patients. Patients who underwent ablation had a lower risk of VT storm compared to those who received anti-arrhythmic drugs [RR: 0.65 with 95% CI (0.49, 0.87), P < 0.01), Compared to anti-arrhythmic drugs, the catheter ablation group also required less Appropriate ICD therapy [RR: 0.72 with 95% CI (0.57, 0.90), P < 0.01), and fewer ICD shocks [ RR: 0.64 with 95% CI (0.45, 0.93), P = 0.02). However, there was no significant difference in VT recurrence [RR: 0.91 with 95% CI (0.74, 1.14), P = 0.42), all-cause mortality [RR: 0.87 with 95% CI (0.65, 1.16), P = 0.34), or any adverse events [RR: 0.96 with 95% CI (0.50, 1.84), P = 0.91) between the two groups.Conclusion:Our meta-analysis showed that catheter ablation was associated with a reduction in VT storm, ICD therapy, and ICD shocks. However, when compared to anti-arrhythmic drugs, catheter ablation for VT in IHD patients did not appear to afford any significant survival advantage.

Circulation, Volume 150, Issue Suppl_1, Page A4143130-A4143130, November 12, 2024. Background:Chagas disease (CD), caused by Trypanosoma cruzi, leads to chronic Chagas cardiomyopathy, one of the deadliest and most debilitating cardiopathies. Benznidazole (BZN) is the medication of choice in Brazil, effective during the acute phase, but its efficacy during the chronic phase is unclear.Aims:To determine if BZN treatment reduces cardiac inflammation and fibrosis via magnetic resonance imaging (MRI) and its association with the circulating immune profile of CD patients.Methods:We collected cardiac images and plasma from a cohort of CD patients before and 6 months after BZN treatment. We performed: 1- MRI of left and right ventricle function and volumes, T1 (MAPA T1), T2 mapping (MAPA T2), and extracellular volume (ECV); 2- analysis of soluble factors including cytokines, chemokines, and growth factors using the Bio-48 Plex Human Cytokine Screening Panel kit. Changes in the variables MAPAT1, MAPAT2, and ECV were used to classify the improvement of CD patients undergoing BZN therapy. Patients with the greatest reductions in these variables post-therapy, compared to pre-therapy, were considered to have greater clinical improvement. Thus, patients were divided into two groups: greater clinical improvement (GCI; n=15) and smaller clinical improvement (SCI; n=15) (figure 1). Data were analyzed using GraphPad Prism 8 software with statistical significance set at p

Circulation, Volume 150, Issue Suppl_1, Page A4139928-A4139928, November 12, 2024. Background:Ketone body metabolism, known for its multifaceted effects, is gaining attention as a potential therapeutic target for cardiovascular diseases. However, the impact of ketone bodies on cardiac hypertrophy and Heart Failure with Preserved Ejection Fraction (HFpEF) remains unclear.Research Questions:To elucidate the effects of ketone bodies on cardiac hypertrophy.The aim of the present research is to investigate the impact of ketone bodies on cardiac hypertrophy induced by metabolic abnormalities using organ-specific ketone body synthesis-deficient mice.Methods:Obesity and hypertension were induced by a high-fat diet combined with NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME) (Combined Stress), and the resultant cardiac hypertrophy and ketone body synthesis were evaluated. Subsequently, organ-specific knockout mice of HMG-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme in ketone body synthesis, were subjected to Combined Stress to assess the impact on cardiac hypertrophy. To conduct a metabolism-focused analysis, cell type-specific nuclei were isolated and subjected to RNA sequencing (RNA-seq) and comprehensive metabolomics analysis. To evaluate the direct effects of ketone bodies, H9C2 cells, rat cardiac cells ,were treated with β-hydroxybutyrate, followed by analysis of oxygen consumption and metabolomics.Results:Combined Stress resulted in increased myocardial cross-sectional area and enhanced ketone body synthesis in the liver and heart. Hepatocyte-specific Hmgcs2 knockout mice (Hmgcs2ΔHep) subjected to Combined Stress exhibited exacerbated myocardial hypertrophy (cardiomyocyte cell size;Hmgcs2flox: 322.8 ± 88.3 μm2:Hmgcs2ΔHep: 444.0 ± 118.5 μm2; p < 0.0001). RNA-seq analysis revealed that the upregulation of glycolytic genes induced by Combined Stress did not occur inHmgcs2ΔHepmice, and a metabolic phenotype favoring fatty acid oxidation persisted. In the liver, hepatocyte destruction and increased serum fatty acid levels were observed. Additionally, H9C2 cells treated with β-hydroxybutyrate showed decreased fatty acid utilization and increased glucose utilization.Conclusion:In cardiac hypertrophy induced by obesity and hypertension, ketone body synthesis mitigates fatty acid overload and promotes glucose utilization, thereby exerting an anti-hypertrophic effect.

Circulation, Volume 150, Issue Suppl_1, Page A4146209-A4146209, November 12, 2024. Background:The management of recurrent pericarditis has evolved to include colchicine and novel anti-interleukin-1 agents, given the limited efficacy of traditional NSAIDs and corticosteroids. We conducted a pairwise and network meta-analysis to evaluate the efficacy and safety of colchicine and anti-IL-1 agents in recurrent pericarditis.Methods:We conducted a comprehensive search on various databases and registries, such as MEDLINE (via PubMed), Embase, and Cochrane Central Register of Controlled Trials (CENTRAL), to retrieve relevant RCTs. We used STATA version 17 to perform meta-analyses under a random-effects model and applied the empirical Bayes (Paule and Mandel) variance estimator to dichotomous data. We performed a network meta-analysis with a placebo/standard therapy group as the comparator in MetaXL 5.3 using the Generalized Pairwise Modeling based on the Bucher method.Results:A total of 6 RCTs were included in the meta-analysis. The risk of pericarditis recurrence was significantly decreased by colchicine (RR 0.46, 95% CI 0.37-0.58) and anti-IL-1 agents (RR 0.13, 95% CI 0.03-0.54) compared to placebo or standard therapy. Colchicine significantly decreased the risk of treatment failure (RR 0.42, 95% CI 0.31-0.57) but did not have a significant impact on the risk of adverse events (RR 1.06, 95% CI 0.31-3.62). No significant risk of adverse events (RR 2.16, 95% CI 0.66-7.01) or serious adverse events (RR 1.01, 95% CI 0.23-4.41) was observed with anti-interleukin-1 agents. Colchicine was also associated with a decreased risk of pericarditis-related rehospitalization (RR 0.26, 95% CI 0.10-0.70). The network meta-analysis showed that anti-IL-1 agents (RR 0.13, 95% CI 0.05 to 0.30) were associated with a greater reduction in pericarditis recurrence than colchicine (RR 0.46, 95% CI 0.37 to 0.59). All anti-interleukin-1 agents significantly decreased the risk of pericarditis recurrence, with comparable efficacies among the different agents.Conclusion:Colchicine and anti-IL-1 agents significantly reduced the risk of pericarditis recurrence with the anti-IL-1 agents demonstrating greater efficacy. Further, high-powered, large-scale RCTs that directly compare various treatment options are needed to confirm or refute our findings.

Circulation, Volume 150, Issue Suppl_1, Page A4142847-A4142847, November 12, 2024. Background:Clonal hematopoiesis of indeterminate potential (CHIP) can contribute to cardiovascular risk. The Interleukin-6 receptor (IL6R) polymorphism (D358A) modifies the risk of coronary artery diseases among CHIP carriers in human cohorts. However, the effects of the IL6R D358A on IL-6 pathways are discordant with the canonical expectation, that the classical IL-6 signaling pathway is anti-inflammatory while the trans-signaling pathway is pro-inflammatory.Hypothesis:DNMT3A, the most frequent driver gene for CHIP, changes the inflammatory consequence of IL-6 classical signaling from anti-inflammatory to pro-inflammatory to worsen atherosclerosis.Method:We investigated if an anti-IL6R antibody modifies atherosclerosis associated with myeloidDnmt3adeficiencyin vivo.Ldlr-/-mice were transplanted with 10% bone marrow cells fromDnmt3a-/-mice/90% of wild-type (WT) cells compared with 100% WT transfer. After engraftment, mice consumed a high-fat diet, and received an anti-IL6R antibody for 10 weeks to assess aortic root atherosclerosis vs. control antibody treatment. We also investigated the differences between IL-6 classical- vs trans-signaling pathways and whetherDnmt3adeficiency in bone marrow-derived macrophages (BMDM) modifies the IL-6 pathways. RNA-seq was performed in BMDM stimulated with IL-6, which activates the classical IL-6 pathway, or IL-6/IL6R conjugate, which activates trans-signaling. We further compared IL-6 vs control stimulation betweenDnmt3a-/-and WT BMDM using RNA-seq, and the major finding was replicated by quantitative PCR. In addition, IL-1β was quantified in the conditioned medium.Result:Anti-IL6R antibody treatment reduced atherosclerosis in the mice with myeloidDnmt3adeficiency. IL4R expression rose significantly in BMDM stimulated by IL-6 compared to IL-6/IL6R conjugate. IL4R induction by IL-6, but not the IL-6/IL6R conjugate, fell significantly inDnmt3a-/-BMDM compared to WT. IL-1β secretion declined with IL-6 stimulation and was higher in IL6R deficient BMDM, but IL-6 stimulation and deletion ofIL6Rdid not affect IL-1β secretion inDnmt3a-/-BMDMs.Conclusion:These data suggest that DNMT3A tonically limits the IL-6 classical pathway to limit atherogenesis in an IL-4 signaling-dependent manner. These findings promote understanding of the CHIP-atherosclerosis association and inform the development of management strategies for CVD risk in CHIP carriers.

Circulation, Volume 150, Issue Suppl_1, Page A4140381-A4140381, November 12, 2024. Introduction:Post-heart Transplant (HTx) ischemia-reperfusion injury (IRI) is associated with an increased risk of rejection and cardiac allograft vasculopathy (CAV). It has been suggested that induction therapy with anti-thymocyte globulin (ATG) may protect against immediate (in the first 30 days) IRI post-HTx. Additionally, ATG has been associated with reduced first-year coronary plaque progression as assessed by intravascular ultrasound (IVUS) among HTx recipients. Whether ATG can decrease first-year intimal thickening in patients experiencing IRI has not been investigated. Therefore, we aim to examine the clinical outcomes of patients who received ATG induction therapy and experienced immediate IRI post-HTx.Methods:Between 2010 and 2020, we assessed 241 patients undergoing HTx and were noted to have immediate post-HTx IRI on their endomyocardial biopsy. Patients were divided into those who received ATG (n=105) induction therapy vs. non-receivers (n=136). In our program, ATG is given to sensitized patients or those with baseline serum creatinine >2.0 mg/dL to delay the initiation of tacrolimus, which may introduce bias to this study. Endpoints included 1-year freedom from any treated rejection (ATR), acute cellular rejection (ACR, grade 2R or 3R), and antibody-mediated rejection (AMR, pAMR grade ≥1, 3-year survival, and 3-year freedom from non-fatal major adverse cardiac events (NF-MACE, including myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, and stroke). IVUS was performed at 4-8 weeks (baseline) and at 1 year post-HTx. Studied IVUS parameters included first-year average change in maximum initial thickness (MIT) and change in MIT ≥0.5mm.Results:Among patients with immediate post-HTx IRI, patients who received ATG induction therapy (57% were sensitized pre-HTx) remained at high immunological risk at 1 year with significantly lower freedom from ATR and AMR but had similar 3-year survival as compared to those who did not receive ATG (Table 1). No between-group differences were observed in the average 1-year change in MIT or the percentage of patients with ≥0.5mm change in MIT.Conclusion:Induction therapy with ATG did not appear to decrease first-year intimal thickening in patients experiencing IRI immediately post-HTx. Future studies are warranted to mitigate immunological complications and reduce coronary plaque progression in high-risk HTx patients.